4-fluoropiperidine orexin receptor antagonists

ABSTRACT

The present invention is directed to 4-fluoropiperidine compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2014/011209, filed Jan. 13, 2014,which claims priority under 35 U.S.C. §119(e) from U.S. Ser. No.61/753,140, filed Jan. 16, 2013.

BACKGROUND OF THE INVENTION

Orexin (hypocretin) neuropeptides are derived from a single gene (HCRT)encoding prepro-orexin that is processed into the mature 33 amino acidorexin A (OX-A) and orexin B (OX-B) peptides (Wong et al., Gen CompEndocrinol, 2011, 171, 124-130). Both neuropeptides have overlappingendogenous specificity for two related G-protein coupled receptors foundthroughout mammals, orexin 1 and orexin 2 receptors (OX₁R and OX₂R,respectively) (Scammell and Winrow, Ann Rev Pharmacol Toxicol, 2011, 51,243-266). OX-A has activity toward both OX₁R and OX₂R having bindingaffinities of 20 and 38 nM, respectively, while OX-B is relativelyspecific for OX₂R, exhibiting 36 nM affinity relative to 420 nM activitytoward OX₁R (Sakurai et al., Cell, 1998, 92, 573-585). Orexin secretingneurons originate from the lateral and posterior areas of thehypothalamus and project to multiple brain regions to affect arousal andvigilance state changes associated with sleep/wake cycles (Scammell andWinrow, Ann Rev Pharmacol Toxicol, 2011, 51, 243-266), but also have thepotential to influence behavior and physiology including feeding,metabolism and gastrointestinal function (Sakurai et al., Cell, 1998,92, 573-585; Tsujino and Sakurai, Pharmacol Rev, 2009, 61, 162-176),reward pathways associated with addiction, learning and memory (Harris,et al., Trends Neurosci., 2006, 29, 571-577), anxiety behaviormodulation (Suzuki et al., Brain Res, 2005, 1044, 116-121), depressionand mood (Scott et al., Behav Brain Res, 2011222, 289-294) and themodulation of migraine and nociception (Akerman et al., Nat RevNeurosci., 2011, 12, 570-84; Mobarakeh et al., Peptides, 2005, 26,767-777).

SUMMARY OF THE INVENTION

The present invention is directed to 4-fluoropiperidine compounds whichare antagonists of orexin receptors, and which are useful in thetreatment or prevention of neurological and psychiatric disorders anddiseases in which orexin receptors are involved. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which orexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A is selected from the group consisting of phenyl, napthyl andheteroaryl;B is selected from the group consisting of phenyl, napthyl andheteroaryl;X is —NR⁴—, —O— or —CH₂—,

-   -   wherein R⁴ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) —C₃₋₆cycloalkyl, and    -   (4) —CF₃;        R^(1a), R^(1b) and R^(1c) may be absent if the valency of A does        not permit such substitution and are independently selected from        the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or napthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R¹⁴,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R¹⁴,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R¹⁴,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R¹⁴,        -   (f) phenyl, which is unsubstituted or substituted with R¹⁴,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R¹⁴,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R^(2a), R^(2b) and R^(2c) may be absent if the valency of B does        not permit such substitution and are independently selected from        the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or napthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R³ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen, and    -   (3) C₁₋₆alkyl, where the alkyl is unsubstituted or substituted        with one or more substituents selected from R¹⁴,        R¹³ is selected from the group consisting of:    -   (1) halogen,    -   (2) hydroxyl,    -   (3) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (4) —O_(n)—(C₁₋₃)perfluoroalkyl,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or napthyl is unsubstituted or substituted with one        or more substituents selected from R¹⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) oxo;        R¹⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH—C₁₋₆alkyl,    -   (8) phenyl,    -   (9) heterocycle,    -   (10) —CO₂H, and    -   (11) —CN;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein A, B, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c) and X aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein A, B, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), and R^(2c) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb′:

wherein A, B, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), and R^(2c) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein A, R^(1a), R^(1b), and R^(1c) are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc′:

wherein A, R^(1a), R^(1b), and R^(1c) are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein A isselected from the group consisting of:

An embodiment of the present invention includes compounds wherein A isselected from the group consisting of: phenyl, pyridyl, pyrimidinyl,pyrazinyl, pyrazolyl, thiazolyl, isothiazolyl, thiophenyl,benzimidazolyl, azabenzimidazolyl, benzimidazolonyl, indazolyl,dihydroindazolonyl, azaindazolyl, indolyl, indolonyl,dihydroisoindolonyl, azaindolyl, benzofuranyl, dihyrobenzofuranyl,benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, imidazopyridinyl,tetrahydroimidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl,imidazothiazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, triazolopyridinyl,triazolopyrimidinyl, and tetrazolopyridinyl. An embodiment of thepresent invention includes compounds wherein A is phenyl. An embodimentof the present invention includes compounds wherein A is pyridyl. Anembodiment of the present invention includes compounds wherein A ispyrazolyl. An embodiment of the present invention includes compoundswherein A is thiazolyl. An embodiment of the present invention includescompounds wherein A is imidazopyridinyl. An embodiment of the presentinvention includes compounds wherein A is benzimidazolyl. An embodimentof the present invention includes compounds wherein A isazabenzimidazolyl. An embodiment of the present invention includescompounds wherein A is indazolyl.

An embodiment of the present invention includes compounds wherein B isselected from the group consisting of:

An embodiment of the present invention includes compounds wherein B isselected from the group consisting of:

-   -   (1) phenyl,    -   (2) quinoline,    -   (3) isoquinoline,    -   (4) benzoxazole,    -   (5) thienopyridine,    -   (6) pyridine,    -   (7) quinazoline,    -   (8) pyrimidine,    -   (9) benzothiazole, and    -   (10) quinoxaline.

An embodiment of the present invention includes compounds wherein B isquinoline. An embodiment of the present invention includes compoundswherein B is isoquinoline. An embodiment of the present inventionincludes compounds wherein B is pyridine. An embodiment of the presentinvention includes compounds wherein B is thienopyridine. An embodimentof the present invention includes compounds wherein B is benzothiazole.An embodiment of the present invention includes compounds wherein B isquinoxaline. An embodiment of the present invention includes compoundswherein B is quinazoline.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        oxazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrazolyl, thiazolyl,        oxadiazolyl, furanyl, tetrazolyl, thiophenyl, pyrrolidinyl,        imidazolidinonyl, oxazolidinonyl, pyrrolidinonyl, pyridyl, and        pyrimidinyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl, amino, or oxo,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, or —O—C₁₋₆alkyl,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, or —O—C₁₋₆alkyl,    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        and —O—C₁₋₆alkyl,    -   (10) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (11) —S—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (12) —CN.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        oxazolyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl,        tetrazolyl, imidazolidinonyl, oxazolidinonyl, pyrrolidinonyl,        pyridyl, and pyrimidinyl, which is unsubstituted or substituted        with halogen, hydroxyl or C₁₋₆alkyl,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl or C₁₋₆alkyl,    -   (8) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (9) —CN.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen    -   (5) triazolyl,    -   (6) oxazolyl,    -   (7) imidazolyl,    -   (8) pyrazolyl,    -   (9) thiazolyl,    -   (10) imidazolidinonyl,    -   (11) pyrimidinyl, and    -   (12) pyridyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) trifluoromethyl,    -   (4) methyl,    -   (5) methoxy,    -   (6) triazolyl,    -   (7) oxazolyl,    -   (8) imidazolyl,    -   (9) pyrazolyl,    -   (10) thiazolyl,    -   (11) imidazolidinonyl,    -   (12) pyrimidinyl, and    -   (13) pyridyl.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        or —O—C₁₋₆alkyl,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, or —O—C₁₋₆alkyl,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, or —O—C₁₋₆alkyl,    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        and —O—C₁₋₆alkyl, and    -   (10) —CN.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (6) —CN.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, and    -   (5) —CN.

An embodiment of the present invention includes compounds wherein R^(2c)is hydrogen, and R^(2a) and R^(2b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) iodo,    -   (5) methoxy,    -   (6) —CN,    -   (7) methyl, and    -   (8) trifluoromethyl.

An embodiment of the present invention includes compounds wherein R³ isfluoro. An embodiment of the present invention includes compoundswherein R³ is hydrogen.

An embodiment of the present invention includes compounds wherein X is—O—. An embodiment of the present invention includes compounds wherein Xis —NH—.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. A group which is designated as being independentlysubstituted with substituents may be independently substituted withmultiple numbers of such substituents. The term “heterocycle” as usedherein includes both unsaturated and saturated heterocyclic moieties,wherein the unsaturated heterocyclic moieties (i.e. “heteroaryl”)include azabenzimidazolyl, azaindazolyl, azaindolyl, benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzothiophenyl,benzoxazepin, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, carbazolyl,carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl,dihyrobenzofuranyl, dihydroindazolonyl, dihydroisoindolonyl,dihydroindolyl, indolazinyl, indazolyl, indolonyl, isobenzofuranyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, imidazopyridinyl,tetrahydroimidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl,imidazothiazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, triazolopyridinyl,triazolopyrimidinyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydroquinoxalinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and N-oxides thereof, and wherein the saturated heterocyclicmoieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxidesthereof.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen such as ²Hand ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N,oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulfur such as³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorinesuch as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizing orexinreceptor activity in a patient such as a mammal in need of suchinhibition comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. In additionto primates, especially humans, a variety of other mammals can betreated according to the method of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for antagonizing orexin receptor activity ortreating the disorders and diseases noted herein in humans and animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of” and or “administering a”compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need thereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionmay be determined in accordance with the following experimental method.For intracellular calcium measurements, Chinese hamster ovary (CHO)cells expressing the rat orexin-1 receptor or the human orexin-2receptor, are grown in Iscove's modified DMEM containing 2 mML-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetalcalf serum (FCS). The cells are seeded at 20,000 cells/well intoBecton-Dickinson black 384-well clear bottom sterile plates coated withpoly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seededplates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 humanorexin-A as the agonist is prepared as a 1 mM stock solution in 1%bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assayat a final concentration of 70 pM. Test compounds are prepared as 10 mMstock solution in DMSO, then diluted in 384-well plates, first in DMSO,then assay buffer. On the day of the assay, cells are washed 3 timeswith 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2)in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronicacid, and 1% BSA. The dye loading solution is then aspirated and cellsare washed 3 times with 100 ul assay buffer. 30 ul of that same bufferis left in each well. Within the Fluorescent Imaging Plate Reader(FLIPR, Molecular Devices), test compounds are added to the plate in avolume of 25 ul, incubated for 5 min and finally 25 ul of agonist isadded. Fluorescence is measured for each well at 1 second intervals for5 minutes and the height of each fluorescence peak is compared to theheight of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A withbuffer in place of antagonist. For each antagonist, IC50 value (theconcentration of compound needed to inhibit 50% of the agonist response)is determined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant(K_(i)) is determined in membranes prepared from CHO cells expressingeither the OX1 or OX2 receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

All of the final compounds of Examples 1-265 herein had activity in theradioligand binding assay with a Ki of about 0.1 nM to 1,000 nM againstthe orexin-1 and/or the orexin-2 receptor. The final compounds ofExamples 1-16, 18, 21, 29, 31, 34, 49, 58, 68, 69, 71, 75-76, 81, 85-88,92, 93, 95-99, 101-130, 132-140, 142-146, 148, 150-153, 155, 156,158-167, 179, 189, 191, 198, 199, 200, 203-206, 209, 230, 231, 234-237,239-244, 246, 248-251, 262, and 264 had activity in the radioligandbinding assay with a Ki of about 0.1 nM to 10 nM against the orexin-1and/or the orexin-2 receptor. All of the final compounds of Examples1-265 herein had activity in the FLIPR assay with an IC50 of about 10 nMto 10,000 nM against the orexin-1 and/or the orexin-2 receptor. Thefinal compounds of Examples 1, 3, 4, 7, 10, 11, 12, 14, 34, 36, 54, 60,71, 72, 74, 75, 76, 81, 85, 88, 92, 93, 95-99, 101, 102, 104-110,112-129, 132-140, 142, 143, 145, 146, 148, 150, 153, 155, 156, 158, 160,162, 165, 166, 167, 198, 199, 230, 231, 233-237, 240, 242, 244, 248-251,and 264 had activity in the FLIPR assay with an IC50 of about 10 nM to100 nM against the orexin-1 and/or the orexin-2 receptor. Such a resultis indicative of the intrinsic activity of the compounds in use asantagonists of the orexin-1 receptor and/or the orexin-2 receptor.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention have utility in treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with orexin receptors,including one or more of the following conditions or diseases: sleepdisorders, sleep disturbances, including enhancing sleep quality,improving sleep quality, increasing sleep efficiency, augmenting sleepmaintenance; increasing the value which is calculated from the time thata subject sleeps divided by the time that a subject is attempting tosleep; improving sleep initiation; decreasing sleep latency or onset(the time it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing intermittent wakings during sleep; decreasingnocturnal arousals; decreasing the time spent awake following theinitial onset of sleep; increasing the total amount of sleep; reducingthe fragmentation of sleep; altering the timing, frequency or durationof REM sleep bouts; altering the timing, frequency or duration of slowwave (i.e. stages 3 or 4) sleep bouts; increasing the amount andpercentage of stage 2 sleep; promoting slow wave sleep; enhancingEEG-delta activity during sleep; decreasing nocturnal arousals,especially early morning awakenings; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersovereating, anorexia, bulimia, cachexia, dysregulated appetite control,hypertension, diabetes, elevated plasma insulin concentrations andinsulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate and colon cancer, osteoarthritis, obstructive sleep apnea,cholelithiasis, gallstones, heart disease, lung disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; sudden death,polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia, metabolic syndrome, also known as syndrome X,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, intestinalmotility dyskinesias, obesity-related gastro-esophageal reflux,hypothalmic diseases, hypophysis diseases, respiratory disorders, suchas obesity-hypoventilation syndrome (Pickwickian syndrome),breathlessness, cardiovascular disorders, inflammation, such as systemicinflammation of the vasculature, arteriosclerosis, hypercholesterolemia,hyperuricaemia, lower back pain, gallbladder disease, gout, kidneycancer, increased anesthetic risk, reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy; diseases or disorders where abnormal oscillatory activityoccurs in the brain, including depression, migraine, neuropathic pain,Parkinson's disease, psychosis and schizophrenia, as well as diseases ordisorders where there is abnormal coupling of activity, particularlythrough the thalamus; enhancing cognitive function, including cognitivedysfunctions that comprise deficits in all types of attention, learningand memory functions occurring transiently or chronically in the normal,healthy, young, adult or aging population, and also occurringtransiently or chronically in psychiatric, neurologic, cardiovascularand immune disorders; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension; congestive heart failure;conditions of the genital/urinary system; disorders of sexual functionand fertility; adequacy of renal function; responsivity to anesthetics;mood disorders, such as depression or more particularly depressivedisorders, for example, single episodic or recurrent major depressivedisorders and dysthymic disorders, or bipolar disorders, for example,bipolar I disorder, bipolar II disorder and cyclothymic disorder, mooddisorders due to a general medical condition, and substance-induced mooddisorders; affective neurosis; depressive neurosis; anxiety neurosis;anxiety disorders including acute stress disorder, agoraphobia,generalized anxiety disorder, obsessive-compulsive disorder, panicattack, panic disorder, post-traumatic stress disorder, separationanxiety disorder, social phobia, specific phobia, substance-inducedanxiety disorder and anxiety due to a general medical condition; acuteneurological and psychiatric disorders such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, ischemicstroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington'sChorea; Huntington's disease and Tourette syndrome; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumour/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; amyotrophic lateralsclerosis; multiple sclerosis; ocular damage; retinopathy; cognitivedisorders; idiopathic and drug-induced Parkinson's disease; muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, seizure disorders, absence seisures,complex partial and generalized seizures; Lennox-Gastaut syndrome;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, trauma, vascular problems or stroke, HIV disease,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; dissociateive disorders including multiplepersonality syndromes and psychogenic amnesias; substance-relateddisorders, substance use, substance abuse, substance seeking, substancereinstatement, all types of psychological and physical addictions andaddictive behaviors, reward-related behaviors (includingsubstance-induced delirium, persisting dementia, persisting amnesticdisorder, psychotic disorder or anxiety disorder; tolerance, addictivefeeding, addictive feeding behaviors, binge/purge feeding behaviors,dependence, withdrawal or relapse from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);appetite, taste, eating or drinking disorders; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, parkinsonism-ALS dementia complex and basal gangliacalcification), chronic fatigue syndrome, fatigue, including Parkinson'sfatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorderor a circadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); neurodegenerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache and other diseases related togeneral orexin system dysfunction.

Thus, in specific embodiments the present invention provides methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of acompound of the present invention.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reducation of risk of the diseases,disorders and conditions noted herein. The dosage of active ingredientin the compositions of this invention may be varied, however, it isnecessary that the amount of the active ingredient be such that asuitable dosage form is obtained. The active ingredient may beadministered to patients (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. perpatient per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; and in yet another embodiment about 5 mg to 50 mg perpatient per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includestherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lonnetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: insulin sensitizers including (i) PPARγantagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor α agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB 1 receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosedescribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone β □agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramnate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl [Leu(28,31)]NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide., (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPAagonists; PDE IV inhibitors; GABA_(A) inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamnfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermnine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art (e.g. PCT PatentPublications WO01/68609, WO2004/085403, WO2005/118548, WO 2008/147518,WO 2010/048012) or as illustrated herein. The following abbreviationsare used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph:phenyl; Bn: benzyl; Ac: acetyl; THF: tetrahydrofuran; DEAD:diethylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; NMM:N-methylmorpholine; DMSO: dimethylsulfoxide; EDC:N-(3-Dimnethylaminopropyl)-N′-ethylcarbodiimide; HOBT:hydroxybenzotriazole hydrate; Boc: tert-butyloxy carbonyl; Et₃N:triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovineserum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide;MTBE: methyl tert-butyl ether; SOCl₂: thionyl chloride; CDI: carbonyldiimidazole; PyClu: 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidiniumhexafluorophosphate; rt: room temperature; HPLC: high performance liquidchromatography. The compounds of the present invention can be preparedin a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

Compounds of the invention are prepared as outlined in Scheme 1.Protected 3-hydroxypiperidine A is alkylated with a 2-halohetercoycleusing NaH as the base to provide B. Some examples 2-halohetercoycles are2-chloroquinolines or 2-fluoroquinolines. Alternative alkylating agents,such as 2-chloropyridines or 2-fluoropyridines, are used to providegeneral structures B. Standard deprotection conditions, e.g. HCl, isused to produce C. Other acids, such as TFA, may also be used to effectthe deprotection. Intermediate C is reacted with a carboxylic acid understandard EDC-HOAT coupling conditions to provide D. Other standardcoupling conditions may be employed in the synthesis of such amides,such as use of an alternative coupling reagent like PyBOP or HATU, oractivation of the carboxylic acid as an acid anhydride or acid chloride.

Alternatively, compounds of the invention are prepared as outlined inScheme 2. Standard deprotection conditions of A, e.g. HCl, is used toproduce E. Intermediate E can be reacted with a carboxylic acid understandard EDC-HOAT coupling conditions to provide F. Other standardcoupling conditions may be employed in the synthesis of such amides,such as use of an alternative coupling reagent like PyBOP or HATU, oractivation of the carboxylic acid as an acid anhydride or acid chloride.Intermediate F is alkylated with a 2-haloheterocycle using NaH as thebase to provide D. Some examples of 2-halohetercoycles are2-chloroquinolines or 2-fluoroquinolines. Alternative alkylating agents,such as 2-chloropyridines or 2-fluoropyridines, may also be used toprovide general structures D.

The carboxylic acids (RCO₂H) and alkylating agents (e.g.2-chloropyridines) used to prepare the compounds of the presentinvention are readily available or they may be obtained from commercialsources or synthesized by methodology familiar to those skilled in theart and as described in the chemical literature. Synthetic routes to theexamples not previously disclosed are outlined in the experimentalsection below.

2-Fluoro-5-(1H-1,2,3-triazol-1-yl)benzoic acid,2-fluoro-5-(2H-1,2,3-triazol-2-yl)benzoic acid, and5-bromo-2-(1H-1,2,3-triazol-1-yl)benzoic acid

A solution of 1,2,3-triazole (63.1 mg, 0.913 mmol),5-bromo-2-fluorobenzoic acid (100 mg, 0.457 mmol), copper(I) iodide(8.70 mg, 0.046 mmol), and potassium carbonate (126 mg, 0.913 mmol) inNMP (2 mL) was heated to 160° C. under microwave radiation for 3 h. Thereaction mixture was filtered and purified by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desired fractions wereconcentrated to yield the title compounds in order of elution:2-fluoro-5-(1H-1,2,3-triazol-1-yl)benzoic acid [MS: m/z=208 (M+1)],5-bromo-2-(1H-1,2,3-triazol-1-yl)benzoic acid [MS: m/z=268, 270 (M+1)],and 2-fluoro-5-(2H-1,2,3-triazol-2-yl)benzoic acid [MS: m/z=208 (M+1)].

3-Fluoro-5-(1H-1,2,3-triazol-1-yl)benzoic acid,3-fluoro-5-(2H-1,2,3-triazol-2-yl)benzoic acid, and3-bromo-5-(1H-1,2,3-triazol-1-yl)benzoic acid

A solution of 1,2,3-triazole (63.1 mg, 0.913 mmol),5-bromo-2-fluorobenzoic acid (100 mg, 0.457 mmol), copper(I) iodide(8.70 mg, 0.046 mmol), and potassium carbonate (126 mg, 0.913 mmol) inNMP (2 mL) was heated to 160° C. under microwave radiation for 13 h. Thereaction mixture was filtered and purified by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desired fractions wereconcentrated to yield the title compounds in order of elution:3-fluoro-5-(1H-1,2,3-triazol-1-yl)benzoic acid [MS: m/z=208 (M+1)],3-bromo-5-(1H-1,2,3-triazol-1-yl)benzoic acid [MS: m/z=268, 270 (M+1)],and 3-fluoro-5-(2H-1,2,3-triazol-2-yl)benzoic acid [MS: m/z=208 (M+1)].

4-(1H-1,2,3-Triazol-1-yl)pyridine-2-carboxylic acid and4-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid

A solution of 1,2,3-triazole (55.0 mg, 0.796 mmol),4-iodopyridine-2-carboxylic acid hydroiodide (150 mg, 0.398 mmol),copper(I) iodide (7.58 mg, 0.040 mmol), and potassium carbonate (165 mg,1.19 mmol) in NMP (2 mL) was heated to 160° C. under microwave radiationfor 7 h. The reaction mixture was filtered and purified by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desired fractions wereconcentrated to yield the title compounds in order of elution:4-(1H-1,2,3-triazol-1-yl)pyridine-2-carboxylic acid [MS: m/z=191 (M+1)]and 4-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid [MS: m/z=191(M+1)].

2-(1H-1,2,3-Triazol-4-yl)benzonitrile

A solution of 2-ethynylbenzonitrile (500 mg, 3.93 mmol), copper(I)iodide (37.4 mg, 0.197 mmol), and trimethylsilyl azide (1.04 mL, 7.87mmol) in DMF (9 mL) and MeOH (0.9 mL) was heated to 100° C. for 22 h.The reaction mixture was poured onto water (50 mL) and extracted withEtOAc (3×50 mL). The combined organics were dried over Na₂SO₄, filtered,and concentrated in vacuo to provide the title compound. MS: m/z=171(M+1).

2-(1H-1,2,3-Triazol-4-yl)benzoic acid

A solution of 2-(1H-1,2,3-triazol-4-yl)benzonitrile (669 mg, 3.93 mmol),and 10M sodium hydroxide (1.97 mL, 19.7 mmol) in dioxane (10 mL) washeated to 100° C. for 18 h. The reaction mixture was concentrated invacuo, dissolved in water (5 mL), and purified by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desired fractions wereconcentrated to yield the title compound. MS: m/z=190 (M+1).

6-Fluoroimidazo[1,2-a]pyridine-8-carboxylic acid

A mixture of 2-amino-5-fluoronicotinic acid (100 mg, 0.641 mmol) and 50%aq. chloroacetaldehyde (0.107 mL, 0.833 mmol) was heated to 60° C. for 2h. The reaction mixture was concentrated in vacuo to yield the titlecompound. MS: m/z=181 (M+1).

2-Amino-4-(trifluoromethyl)nicotinic acid

A mixture of 2-chloro-4-(trifluoromethyl)nicotinic acid (1.00 g, 4.43mmol) and 7M ammonia in MeOH (15.0 mL, 105 mmol) in a steel pressurebomb was heated to 120° C. for 18 h and 160° C. for 20 h. The reactionmixture was concentrated in vacuo, then dissolved in 10% HCl (5 mL) andpurified directly by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desiredfractions were concentrated to yield the title compound. MS: m/z=207(M+1).

7-(Trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxylic acid

A mixture of 2-amino-4-(trifluoromethyl)nicotinic acid (74.0 mg, 0.359mmol) and 50% aq. chloroacetaldehyde (0.093 mL, 0.718 mmol) was heatedto 80° C. for 18 h. The reaction mixture was concentrated in vacuo toyield the title compound. MS: m/z=231 (M+1).

2-Amino-6-(trifluoromethyl)nicotinic acid hydrochloride

A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (1.00 g, 4.43mmol) and 7M ammonia in MeOH (20.0 mL, 140 mmol) in a steel pressurebomb was heated to 120° C. for 64 h. The reaction mixture wasconcentrated in vacuo, then added 10% HCl (5 mL) and the resulting solidwas filtered, washed with 10% HCl (2×5 mL) and dried to yield the titlecompound. MS: m/z=207 (M+1).

5-(Trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxylic acid

A mixture of 2-amino-6-(trifluoromethyl)nicotinic acid (114 mg, 0.470mmol) and 50% aq. chloroacetaldehyde (0.121 mL, 0.940 mmol) was heatedto 80° C. for 18 h. The reaction mixture was concentrated in vacuo toyield the title compound. MS: m/z=231 (M+1).

7-Chloroimidazo[1,2-a]pyridine-8-carboxylic acid

A mixture of 2-amino-4-chloronicotinic acid hydrochloride (153 mg, 0.732mmol) and 50% aq. chloroacetaldehyde (0.369 mL, 2.86 mmol) was heated to60° C. for 26 h. The reaction mixture was purified directly by HPLCusing a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desired fractions wereconcentrated to yield the title compound. MS: m/z=197 (M+1).

6-(Trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxylic acid

A mixture of 2-amino-5-trifluoronicotinic acid hydrochloride (100 mg,0.485 mmol) and 50% aq. chloroacetaldehyde (0.125 mL, 0.970 mmol) washeated to 80° C. for 18 h. The reaction mixture was concentrated invacuo to yield the title compound. MS: m/z=231 (M+1).

[1,2,3]Triazolo[1,5-a]pyridine-7-carboxylic acid

To a solution of 7-bromo[1,2,3]triazolo[1,5-a]pyridine (172 mg, 0.869mmol) in THF (2 mL) at −78° C. was added tert-butyllithium (1.12 mL,1.91 mmol, 1.7 M) and the solution was stirred for 1 h. The reactionmixture was poured onto crushed dried ice and allowed to warm to ambienttemperature. The resulting yellow solid was filtered, washed with THF(2×3 mL), and dried to yield the title compound. MS: m/z=164 (M+1).

4-(1,3-Oxazol-2-yl)pyridine-2-carboxylic acid

A solution of methyl 4-bromopicolinate (100 mg, 0.463 mmol),2-(tributylstannyl)oxazole (249 mg, 0.694 mmol), andtetrakis(triphenylphosphine)palladium (26.7 mg, 0.023 mmol) in dioxane(2 mL) was heated to 150° C. under microwave radiation for 15 min. Tothe reaction mixture was added 10M sodium hydroxide (0.140 mL, 1.40mmol) and the solution was heated to 60° C. for 18 h. The reactionmixture was concentrated in vacuo, dissolved in water (3 mL), filtered,and purified by HPLC using a reversed phase C18 column and eluting witha gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desiredfractions were concentrated to yield the title compound. MS: m/z=191(M+1).

tert-Butyl(3S,4R)-4-fluoro-3-(quinolin-2-ylamino)piperidine-1-carboxylate

A solution of methyl 2-chloroquinoline (15.0 mg, 0.092 mmol), tert-butyl(3S,4R)-3-amino-4-fluoropiperidine-1-carboxylate (31.1 mg, 0.101 mmol),bis(tri-tert-butylylphosphine)palladium (1.8 mg, 0.0037 mmol), andtripotassium phosphate (58.4 mg, 0.275 mmol) in DMA (0.2 mL) was heatedto 100° C. for 20 h. The reaction mixture was filtered, and purified byHPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desired fractions wereconcentrated to yield the title compound. MS: m/z=346 (M+1).

N-[(3S,4R)-4-Fluoropiperidin-3-yl]quinolin-2-amine dihydrochloride

4M HCl in dioxane (0.724 mL, 2.90 mmol) was added to tert-butyl(3S,4R)-4-fluoro-3-(quinolin-2-ylamino)piperidine-1-carboxylate (10 mg,0.029 mmol) and the solution was stirred at ambient temperature for 2 h.The reaction mixture was concentrated in vacuo to provide the titlecompound as a white solid. MS: m/z=246 (M+1).

Example 1

tert-Butyl(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidine-1-carboxylate

Sodium hydride (2.36 g, 59.0 mmol) was added to a solution of tert-butyl(3S)-4,4-difluoro-3-hydroxypiperidine-1-carboxylate (7.00 g, 29.5 mmol)in DMSO (10 mL) and the solution was stirred at ambient temperature for0.5 h. 2-Chloroquinoline (5.79 g, 35.4 mmol) was added and the solutionwas stirred for 18 h. The reaction mixture was poured onto water (500mL) and extracted with Et₂O (3×150 mL). The combined organics were driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude was purifieddirectly by column chromatography on silica gel, eluting with Hex:EtOAc100:0→80:20 to provide the title compound as a white solid. MS: m/z=365(M+1).

2-{[(3S)-4,4-Difluoropiperidin-3-yl]oxy}quinoline dihydrochloride

4M HCl in dioxane (70.7 mL, 283 mmol) was added to tert-butyl(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidine-1-carboxylate (10.3 g,28.3 mmol) and the suspension was stirred at ambient temperature for 72h. The reaction mixture was concentrated in vacuo to provide the titlecompound as a white solid. MS: m/z=265 (M+1).

(3S)-(4,4-Difluoro-3-(quinolin-2-yloxy)piperidin-1-yl)(2,6-difluoro-3-methoxyphenyl)methanone

A solution of EDC (6.82 mg, 0.036 mmol), HOAT (4.84 mg, 0.036 mmol),DIEA (0.026 mL, 0.148 mmol), 2,6-difluoro-3-methoxybenzoic acid (7.25mg, 0.039 mmol) was stirred in DMF (0.5 mL) for 0.5 h, followed by theaddition of 2-{[(3S)-4,4-difluoropiperidin-3-yl]oxy}quinolinedihydrochloride (10.0 mg, 0.030 mmol). The solution was stirred for 6 hat ambient temperature, then purified directly by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desired fractions wereconcentrated to yield the title compound as the trifluoroacetate salt.MS: m/z=435 (M+1); HRMS: m/z=435.1308 (M+1); calculated m/z=435.1326(M+1) for C₂₂H₁₉F₄N₂O₃.

Example 2

(3S)-4,4-Difluoropiperidin-3-ol hydrochloride

4M HCl in dioxane (19.6 mL, 78 mmol) was added to tert-butyl(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidine-1-carboxylate (6.19 g,26.1 mmol) and the suspension was stirred at ambient temperature for 1h. The resulting white solid was filtered, washed with dioxane (2×20mL), and dried provide the title compound as a white solid.

(S)-(3-(1H-1,2,3-Triazol-1-yl)phenyl)(4,4-difluoro-3-hydroxypiperidin-1-yl)methanone

A solution of EDC (970 mg, 5.06 mmol), HOAT (689 g, 5.06 mmol), DIEA(3.68 mL, 21.1 mmol), and 3-(1H-1,2,3-triazol-1-yl)benzoic acid (798 mg,4.22 mmol) was stirred in DMF (5 mL) for 0.5 h, followed by the additionof (3S)-4,4-difluoropiperidin-3-ol hydrochloride (732 mg, 4.22 mmol) inDMF (0.5 mL). The solution was stirred for 16 h at ambient temperature,then filtered and concentrated in vacuo. The crude was purified bycolumn chromatography on silica gel, eluting with DCM:EtOAc 100:0→0:100to provide the title compound as a white solid. MS: m/z=309 (M+1).

(S)-(3-(1H-1,2,3-Triazol-1-yl)phenyl)(3-(benzo[d]thiazol-2-yloxy)-4,4-difluoropiperidin-1-yl)methanone

Sodium hydride (5.19 mg, 0.130 mmol) was added to a solution of(S)-(3-(1H-1,2,3-triazol-1-yl)phenyl)(4,4-difluoro-3-hydroxypiperidin-1-yl)methanone(20.0 mg, 0.065 mmol) in DMSO (1 mL) and the solution was stirred atambient temperature for 0.5 h. 2-chlorobenzothiazole (13.0 mg, 0.078mmol) was added and the solution was stirred for 16 h at ambienttemperature. The reaction mixture was purified directly by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1 The desired fractions wereconcentrated to yield the title compound as the trifluoroacetate salt.MS: m/z=442 (M+1); HRMS: m/z=442.1133 (M+1); calculated m/z=442.1144(M+1) for C₂₁H₁₈F₂N₅O₂S₁.

TABLE 1 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 1, butsubstituting the appropriate acid for 2,6-difluoro-3-methoxybenzoic acid(Step 3) and the appropriate alkylating agent for 2-chloroquinoline(Step 1), as described in the foregoing Reaction Schemes and Examples.The requisite starting materials were commercially available, describedin the literature or readily synthesized by one skilled in the art oforganic synthesis from commercially available reagents usingconventional reactions without undue experimentation. MS ExampleStructure Name (M + 1) 3

2-[(4,4-difluoro-1-{[5- methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline 450 4

2-[(3S)-(4,4-difluoro-1-{[2- (2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline 436 5

2-({4,4-difluoro-1-[(5- fluoro-2-pyrimidin-2-ylphenyl)carbonyl]piperidin- 3-yl}oxy)quinoline 465 6

2-({4,4-difluoro-1-[(4- fluoro-2-pyrimidin-2-ylphenyl)carbonyl]piperidin- 3-yl}oxy)quinoline trifluoroacetate 465 7

2-[(4,4-difluoro-1-{[2-(3- methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 451 8

2-[(1-{[5-bromo-2-(2H- 1,2,3-triazol-2- yl)phenyl]carbonyl}-4,4-difluoropiperidin-3- yl)oxy]quinoline trifluoroacetate 514, 516 9

2-[(1-{[5-chloro-2-(2H- 1,2,3-triazol-2- yl)phenyl]carbonyl}-4,4-difluoropiperidin-3- yl)oxy]quinoline trifluoroacetate 470 10

2-[(4,4-difluoro-1-{[3- methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 450 11

2-[(4,4-difluoro-1-{[3-(1,3- thiazol-4-yl)pyridin-2-yl]carbonyl}piperidin-3- yl)oxy]quinoline trifluoroacetate 453 12

2-[(4,4-difluoro-1-{[2-(1,3- thiazol-2- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 452 13

2-[(4,4-difluoro-1-{[2-(1,3- thiazol-5- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 452 14

2-[(4,4-difluoro-1-{[2-(1,3- oxazol-2- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 436 15

2-[(4,4-difluoro-1-{[2-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 451 16

2-[(4,4-difluoro-1-{[2-(1- methyl-1H-pyrazol-4-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 449 17

2-{[4,4-difluoro-1- (quinolin-6- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 420 18

3-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}phenoltnfluoroacetate 385 19

2-({4,4-difluoro-1-[(2- fluorophenyl)carbonyl]piper-idin-3-yl}oxy)quinoline trifluoroacetate 387 20

2-({4,4-difluoro-1-[(2- methylphenyl)carbonyl]piper-idin-3-yl}oxy)quinoline trifluoroacetate 383 21

2-[(4,4-difluoro-1-{[2- (trifluoromethyl)phenyl]car- bonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 437 22

2-({4,4-difluoro-1-[(3- methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 399 23

2-({1-[(2- ethoxyphenyl)carbonyl]-4,4- difluoropiperidin-3-yl}oxy)quinoline trifluoroacetate 413 24

2-({4,4-difluoro-1-[(3- methylphenyl)carbonyl]piper-idin-3-yl}oxy)quinoline trifluoroacetate 383 25

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}benzonitrile trifluoroacetate 394 26

2-({1-[(3- cyclopropylphenyl)carbonyl]- 4,4-difluoropiperidin-3-yl}oxy)quinoline trifluoroacetate 409 27

2-[(4,4-difluoro-1-{[2- (methylsulfanyl)phenyl] carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 415 28

2-[(4,4-difluoro-1-{[2-(1H- imidazol-1- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 435 29

2-[(4,4-difluoro-1-{[2-(1H- 1,2,4-triazol-5-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 436 30

2-[(4,4-difluoro-1-{[2-(1H- imidazol-2- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 435 31

2-[(4,4-difluoro-1-{[2-(1H- pyrazol-4- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 435 32

2-({4,4-difluoro-1-[(2- methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 399 33

2-[(4,4-difluoro-1-{[2-(1H- 1,2,4-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 436 34

2-[(4,4-difluoro-1-{[2- (methylsulfanyl)-1H- benzimidazol-7-yl]carbonyl}piperidin-3- yl)oxy]quinoline trifluoroacetate 455 35

2-{[4,4-difluoro-1-(1H- indazol-7- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 409 36

2-({4,4-difluoro-1-[(2- pyrazin-2- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 447 37

2-({4,4-difluoro-1-[(3- methyl-1H-indol-4- yl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 422 38

2-[(4,4-difluoro-1-{[2- methyl-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}- piperidin-3- yl)oxy]quinoline trifluoroacetate450 39

2-[(4,4-difluoro-1-{[2- fluoro-6-(1,3-thiazol-4-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 470 40

2-[(4,4-difiuoro-1-{[5- fluoro-2-(1,3-thiazol-4-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 470 41

2-{[4,4-difluoro-1- (imidazo[1,2-a]pyrazin-5- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 410 42

2-{[4,4-difluoro-1- ([1,2,4]triazolo[1,5- a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 43

3-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-2-fluorophenol trifluoroacetate 403 44

2-[(4,4-difluoro-1-{[4-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3- yl)oxy]quinoline trifluoroacetate 437 45

2-[(4)4-difluoro-1-{[2- fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}- piperidin-3- yl)oxy]quinoline trifluoroacetate454 46

[3-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(2H-1,2,3- triazol-2- yl)phenyl]methanoltrifluoroacetate 466 47

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3- yl)oxy]quinoline trifluoroacetate 442 48

2-[(4,4-difluoro-1-{[3-(2H- 1,2,3-triazol-2-yl)thiophen-2-yl]carbonyl}piperidin-3- yl)oxy]quinoline trifluoroacetate 442 49

2-[(4,4-difluoro-1-{[2-(4- methyl-1H-pyrazol-1-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 449 50

2-{[4,4-difluoro-1- (tetrazolo[1,5-a]pyridin-8- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 411 51

2-({4,4-difluoro-1-[(4- pyrrolidin-1-ylpyridin-2-yl)carbonyl]piperidin-3- yl}oxy)quinoline 439 52

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-4-(1H-pyrazol-1-yl)phenol 451 53

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-4-(1H-imidazol-4-yl)phenol 451 54

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-4-(1,3-thiazol-4-yl)phenol 468 55

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-4-(1H-pyrazol-3-yl)phenol 451 56

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-4-(1,3-oxazol-4-yl)phenol 452 57

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-4-(1,3-oxazol-2-yl)phenol 452 58

2-[(1-{[2-chloro-5-(1H- pyrazol-1- yl)phenyl]carbonyl}-4,4-difluoropiperidin-3- yl)oxy]quinoline 469 59

2-({4,4-difluoro-1-[(5- furan-2-yl-1-methyl-1H- pyrazol-3-yl)carbonyl]piperidin-3- yl}oxy)quinoline 439 60

2-[(4,4-difluoro-1-{[3-(1,3- oxazol-5- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 436 61

2-({1-[(2,6- dimethoxyphenyl)carbonyl]- 4,4-difluoropiperidin-3-yl}oxy)quinoline trifluoroacetate 429 62

2-({1-[(5-chloro-2- methylphenyl)carbonyl]- 4,4-difluoropiperidin-3-yl}oxy)quinoline trifluoroacetate 417 63

2-({1-[(2,5- difluorophenyl)carbonyl]- 4,4-difluoropiperidin-3-yl}oxy)quinoline trifluoroacetate 405 64

2-({4,4-difluoro-1-[(2- fluoro-6- methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 417 65

2-{[1-(2,3-dihydro-1- benzofuran-7-ylcarbonyl)- 4,4-difluoropiperidin-3-yl]oxy}quinoline trifluoroacetate 411 66

2-({4,4-difluoro-1-[(2- fluoro-3- methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 417 67

2-({1-[(2,3- difluorophenyl)carbonyl]- 4,4-difluoropiperidin-3-yl}oxy)quinoline trifluoroacetate 405 68

2-({4,4-difluoro-1-[(2- methoxy-5-methyl- phenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 413 69

2-[(4,4-difluoro-1-{[3-(1H- imidazol-1- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 435 70

2-({4,4-difluoro-1-[(3- furan-2- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 435 71

2-({4,4-difluoro-1-[(3- methoxy-5- methylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 413 72

2-({4,4-difluoro-1-[(2- methyl-1-benzofuran-7- yl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 423 73

2-{[4,4-difluoro-1-(1H- imidazo[4,5-c]pyridin-7- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 410 74

2-{[(3S)-4,4-difluoro-1- (pyrazolo[1,5-a]pyridin-7-ylcarbonyl)piperidin-3- yl]oxy}quinoline hydrochloride 409 75

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline hydrochloride 436 76

2-({(3S)-4,4-difluoro-1-[(2- fluoro-5- methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline hydrochloride 417 77

2-{[4,4-difluoro-1- (imidazo[2,1-b][1,3]thiazol-6-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 415 78

2-({(3S)-4,4-difluoro-1-[(2- methyl-2H-indazol-3-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 423 79

2-{[(3S)-1-(1,2- benzisoxazol-3-ylcarbonyl)- 4,4-difluoropiperidin-3-yl]oxy}quinoline trifluoroacetate 410 80

2-({(3S)-4,4-difluoro-1-[(2- phenylpyridin-3- yl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 446 81

2-({(3S)-4,4-difluoro-1-[(4- phenylpyridin-3- yl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 446 82

2-{[(3S)-4,4-difluoro-1- (pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 83

2-{[(3S)-4,4-difluoro-1- (pyrazolo[1,5-a]pyridin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 84

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[2,3-b]pyridin-2-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 85

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[3,2-b]pyridin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline hydrochloride 409 86

2-{[(3S)-4,4-difluoro-1- (1H-indol-3- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 408 87

2-{[(3S)-4,4-difluoro-1- (1H-indazol-3- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 409 88

2-({(3S)-4,4-difluoro-1-[(1- methyl-1H-indazol-3-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 423 89

2-{[(3S)-4,4-difluoro-1- (imidazo[1,5-a]pyridin-1-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 90

2-{[(3S)-4,4-difluoro-1- (imidazo[1,5-a]pyridin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 91

2-{[(3S)-4,4-difluoro-1- (5H-pyrrolo[2,3-b]pyrazin-7-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 92

2-{[(3S)-4,4-difluoro-1-{[3- (2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline hydrochloride 436 93

4-(3-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}phenyl)-1,3- thiazol-2-amine trifluoroacetate 467 94

2-{[(3S)-4,4-difluoro-1-{[2- (1H-tetrazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 437 95

2-{[(3S)-4,4-difluoro-1-{[2- (2H-tetrazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 437 96

2-{[(3S)-4,4-difluoro-1-{[2- fluoro-5-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}- piperidin-3- yl]oxy}quinoline trifluoroacetate454 97

2-{[(3S)-4,4-difluoro-1-{[2- fluoro-5-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}- piperidin-3- yl]oxy}quinoline trifluoroacetate454 98

2-{[(3S)-1-{[5-bromo-2- (1H-1,2,3-triazol-1- yl)phenyl]carbonyl}-4,4-difluoropiperidin-3- yl]oxy}quinoline trifluoroacetate 514, 516 99

2-{[(3S)-4,4-difluoro-1-{[2- fluoro-5-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 453100

2-{[(3S)-4,4-difluoro-1-{[3- (1,2,4-oxadiazol-3-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 437 101

2-{[(3S)-4,4-difluoro-1-{[3- (1,3-oxazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 436102

(3S)-(4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl)(imidazo[1,2-a]pyridin- 8-yl)methanone 409 102

2-({(3S)-1-[(2,6-difluoro-3- methoxyphenyl)carbonyl]-4,4-difluoropiperidin-3- yl}oxy)quinoline trifluoroacetate 435 103

2-{[(3S)-4,4-difluoro-1-{[3- fluoro-5-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}- piperidin-3- yl]oxy}quinoline trifluoroacetate454 104

2-{[(3S)-4,4-difluoro-1-{[3- fluoro-5-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}- piperidin-3- yl]oxy}quinoline trifluoroacetate454 105

2-{[(3S)-1-{[3-bromo-5- (1H-1,2,3-triazol-1- yl)phenyl]carbonyl}-4,4-difluoropiperidin-3- yl]oxy}quinoline 514 106

2-{[(3S)-4,4-difluoro-1-{[4- (1H-1,2,3-triazol-1- yl)pyridin-2-yl]carbonyl}piperidin-3- yl]oxy}quinoline trifluoroacetate 437 107

2-{[(3S)-4,4-difluoro-1-{[4- (2H-1,2,3-triazol-2- yl)pyridin-2-yl]carbonyl}piperidin-3- yl]oxy}quinoline trifluoroacetate 437 108

2-({(3S)-1-[(3- chloroimidazo[1,2- a]pyridin-8-yl)carbonyl]-4,4-difluoropiperidin-3- yl}oxy)quinoline 443 109

2-{[(3S)-4,4-difluoro-1-{[3- (1,3-thiazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 452 110

2-{[(3S)-4,4-difluoro-1-{[3- (1H-pyrazol-3-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 435 111

2-{[(3S)-4,4-difluoro-1-{[3- (2-methyl-1,3-thiazol-4-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 466 112

2-{[(3S)-4,4-difluoro-1-{[4- (1H-imidazol-1-yl)pyridin-2-yl]carbonyl}piperidin-3- yl]oxy}quinoline 436 113

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,4-triazol-5-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 436 114

2-({(3S)-4,4-difluoro-1-(2- pyridin-3- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline 446 115

2-{[(3S)-1-(1H- benzimidazol-4-ylcarbonyl)- 4,4-difluoropiperidin-3-yl]oxy}quinoline hydrochloride 409 116

2-({(3S)-4,4-difluoro-1-[(1- methyl-1H-indazol-4-yl)carbonyl]piperidin-3- yl}oxy)quinoline 423 117

1-(3-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}phenyl)- imidazolidin-2-one 453 118

2-{[(3S)-4,4-difluoro-1-{[2- (1H-pyrazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 435 119

2-({(3S)-4,4-difluoro-1-[(3- phenylpyridin-4- yl)carbonyl]piperidin-3-yl}oxy)quinoline 446 120

2-{[(3S)-4,4-difluoro-1-{[3- (1H-pyrazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 435 121

2-{[(3S)-4,4-difluoro-1-{[3- (1H-pyrazol-4-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 435 122

2-({(3S)-1-[(2,5- dimethoxyphenyl)carbonyl]- 4,4-difluoropiperidin-3-yl}oxy)quinoline 429 123

2-{[(3S)-4,4-difluoro-1-{[3- (1H-imidazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 435 124

2-({(3S)-4,4-difluoro-1-[(3- phenylpyridin-2- yl)carbonyl]piperidin-3-yl}oxy)quinoline 446 125

2-{[(3S)-1-(1H- benzimidazol-5-ylcarbonyl)- 4,4-difluoropiperidin-3-yl]oxy}quinoline 409 126

2-{[(3S)-4,4-difluoro-1- (1H-indazol-4- ylcarbonyl)piperidin-3-yl]oxy}quinoline 409 127

2-{[(3S)-4,4-difluoro-1-{[3- fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 454 128

2-{[(3S)-4,4-difluoro-1-{[2- (5-methyl-2H-tetrazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 451 129

2-{[(3S)-1-{[2-chloro-5- (4H-1,2,4-triazol-4- yl)phenyl]carbonyl}-4,4-difluoropiperidin-3- yl]oxy}quinoline trifluoroacetate 470 130

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-4-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 436131

2-{[(3S)-1-(1,3-benzoxazol- 4-ylcarbonyl)-4,4- difluoropiperidin-3-yl]oxy}quinoline 410 132

2-({(3S)-4,4-difluoro-1-[(2- pyridin-2- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline 446 133

2-{[(3S,4S)-4-fluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 391 134

2-{[(3S,4S)-4-fluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 418135

2-{[(3S)-4,4-difluoro-1-{[6- (1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}piperidin-3- yl]oxy}quinoline trifluoroacetate 436 136

2-{[(3S)-4,4-difluoro-1-{[4- (1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}piperidin-3- yl]oxy}quinoline trifluoroacetate 436 137

1-(3-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4- fluorophenyl)imidazolidin- 2-one hydrochloride 471 138

2-{[(3S)-4,4-difluoro-1-{[2- (1H-1,2,3-triazol-5-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline hydrochloride 436 139

1-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyrazin-8-ylcarbonyl)piperidin-3- yl]oxy}quinoline hydrochloride 410 140

2-{[(3S)-4,4-difluoro-1- (1H-imidazo[4,5-c]pyridin-4-ylcarbonyl)piperidin-3- yl]oxy}quinoline hydrochloride 410 141

2-({(3S)-4,4-difluoro-1-[(3- pyrimidin-2- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline 447 142

2-({(3S)-4,4-difluoro-1-[(2- methyl-1H-benzimidazol-4-yl)carbonyl]piperidin-3- yl}oxy)quinoline 423 143

2-({(3S)-4,4-difluoro-1-[(6- fluoro-1H-benzimidazol-4-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 427 144

2-({(3S)-4,4-difluoro-1-[(2- pyridin-4- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 446 145

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}-6-fluoro-1,3- benzothiazole 460146

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-6-fluoro-1,3- benzothiazoletrifluoroacetate 433 147

7-{[(3S)-4,4-difluoro-3-{[5- (trifluoromethyl)pyridin-2-yl]oxy}piperidin-1- yl]carbonyl}pyrazolo[1,5- a]pyridinetrifluoroacetate 427 148

2-({(3S)-4,4-difluoro-1-[(6- fluoroimidazo[1,2- a]pyridin-8-yl)carbonyl]piperidin-3- yl}oxy)quinoline hydrochloride 427 149

2-({(3S)-4,4-difluoro-1-[(2- pyrimidin-5- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 447 150

2-{[(3S)-4,4-difluoro-1-{[4- (1,3-oxazol-2-yl)pyridin-2-yl]carbonyl}piperidin-3- yl]oxy}quinoline trifluoroacetate 437 151

7-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3- benzoxazol-2(3H)-one trifluoroacetate 426 152

2-{[(3S)-4,4-difluoro-1-{[2- (trifluoromethyl)-1H- benzimidazol-4-yl]carbonyl}piperidin-3- yl]oxy}quinoline trifluoroacetate 477 153

2-({(3S)-1-[(7- chloroimidazo[1,2- a]pyridin-8-yl)carbonyl]-4,4-difluoropiperidin-3- yl}oxy)quinoline trifluoroacetate 443 154

3-(3-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}phenyl)-1,3- oxazolidin-2-one hydrochloride 454 155

2-({(3S)-1-[(6- chloroimidazo[1,2- a]pyridin-8-yl)carbonyl]-4,4-difluoropiperidin-3- yl}oxy)quinoline hydrochloride 443 156

2-{[(3S)-4,4-difluoro-1- (1H-pyrazolo[4,3-c]pyridin-4-ylcarbonyl)piperidin-3- yl]oxy}quinoline hydrochloride 410 157

2-{[(3S)-4,4-difluoro-1- (1H-pyrazolo[3,4-b]pyridin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 158

2-{[(3S)-4,4-difluoro-1-{[7- (trifluoromethyl)imidazo[1,2- a]pyridin-8-yl]carbonyl}piperidin-3- yl]oxy}quinoline hydrochloride 477 159

2-({(3S)-4,4-difluoro-1-[(3- iodoimidazo[1,2-a]pyridin-8-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 535 160

3-(3-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4- fluorophenyl)-1,3- oxazolidin-2-one trifluoroacetate472 161

1-(3-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4- fluorophenyl)pyrrolidin-2- one trifluoroacetate 470162

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[2,3-c]pyridin-4-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 163

2-{[(3S)-4,4-difluoro-1- (7H-pyrrolo[2,3- d]pyrimidin-4-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 164

2-{[(3S)-4,4-difluoro-1- (1H-indol-4- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 408 165

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[2,3-b]pyridin-4-ylcarbonyl)piperidin-3- yl]oxy}quinoline 409 166

2-{[(3S)-4,4-difluoro-1- ([1,2,3]triazolo[1,5- a]pyridin-7-ylcarbonyl)piperidin-3- yl]oxy}quinoline 410 167

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[3,2-c]pyridin-4-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 168

1-(3-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4,6- difluorophenyl)imidazolidin- 2-one trifluoroacetate489 169

4-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3-dihydro- 2H-indol-2-one 424 170

2-({(3S)-4,4-difluoro-1-[(5- methylpyrazolo[1,5- a]pyrimidin-7-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 424 171

2-{[(3S)-4,4-difluoro-1- (1H-imidazo[4,5-c]pyridin-6-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 172

2-{[(3S)-1-(1,3- benzothiazol-5-ylcarbonyl)- 4,4-difluoropiperidin-3-yl]oxy}quinoline 426 173

2-{[(3S)-4,4-difluoro-1- (1H-imidazo[4,5-b]pyridin-6-ylcarbonyl)piperidin-3- yl]oxy}quinoline 410 174

2-{[(3S)-4,4-difluoro-1- (pyrazolo[1,5-a]pyridin-2-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 175

2-{[(3S)-4,4-difluoro-1- (1H-indazol-5- ylcarbonyl)piperidin-3-yl]oxy}quinoline 409 176

2-{[(3S)-4,4-difluoro-1- (1H-indazol-6- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 409 177

2-{[(3S)-1-(2,1- benzisothiazol-3- ylcarbonyl)-4,4- difluoropiperidin-3-yl]oxy}quinoline trifluoroacetate 426 178

2-{[(3S)-1-(2,1- benzisoxazol-3-ylcarbonyl)- 4,4-difluoropiperidin-3-yl]oxy}quinoline trifluoroacetate 410 179

2-({4,4-difluoro-1-[(2- methyl-5-phenyl-1,3- thiazol-4-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 466 180

2-{[4,4-difluoro-1- ([1,2,4]triazolo[4,3- a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 181

2-({4,4-difluoro-1-[(6- methylimidazo[2,1- b][1,3]thiazol-3-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 429 182

2-[(4,4-difluoro-1-{[4-(2H- 1,2,3-triazol-2-yl)isothiazol-3-yl]carbonyl}piperidin-3- yl)oxy]quinoline trifluoroacetate 443 183

2-[(4,4-difluoro-1-{[3- methyl-5-(2H-1,2,3-triazol- 2-yl)isothiazol-4-yl]carbonyl}piperidin-3- yl)oxy]quinoline trifluoroacetate 457 184

2-{[l-(1H-benzotriazol-5- ylcarbonyl)-4,4- difluoropiperidin-3-yl]oxy}quinoline trifluoroacetate 410 185

2-[(4,4-difluoro-1-{[3-(1H- 1,2,4-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 436186

2-{[4,4-difluoro-1- (imidazo[1,5-a]pyridin-5- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 409 187

2-{[4,4-difluoro-1-(pyrazin- 2-ylcarbonyl)piperidin-3- yl]oxy}quinolinetrifluoroacetate 371 188

2-{[4,4-difluoro-1- (pyrimidin-2- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 371 189

2-{[l-(biphenyl-2- ylcarbonyl)-4,4- difluoropiperidin-3-yl]oxy}quinoline trifluoroacetate 445 190

2-[(4,4-difluoro-1-{[2- (trifluoromethoxy)phenyl] carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 453 191

2-{[4,4-difluoro-1-(1H- indol-7- ylcarbonyl)piperidin-3-yl]oxy}quinoline trifluoroacetate 408 192

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-2-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 193

2-{[(3S)-4,4-difluoro-1- (pyrazolo[1,5-a]pyrimidin-2-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 194

2-{[(3S)-4,4-difluoro-1- ([1,2,4]triazolo[1,5- a]pyrimidin-2-ylcarbonyl)piperidin-3- yl]oxy}quinoline 411 195

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[3,2-b]pyridin-2-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 196

2-{[(3S)-4,4-difluoro-1- (imidazo[1,5-b]pyridazin-7-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 197

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-b]pyridazin-2-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 198

2-({(3S)-4,4-difluoro-1-[(l- methyl-1H-benzimidazol-4-yl)carbonyl]piperidin-3- yl}oxy)quinoline hydrochloride 423 199

2-({(3S)-4,4-difluoro-1-[(l- methyl-1H-imidazo[4,5- c]pyridin-4-yl)carbonyl]piperidin-3- yl}oxy)quinoline hydrochloride 424 200

2-{[(3S)-4,4-difluoro-1-{[6- (trifluoromethyl)imidazo[1,2- a]pyridin-8-yl]carbonyl}piperidin-3- yl]oxy}quinoline hydrochloride 477 201

2-{[(3S)-4,4-difluoro-1-{[3- (1,2,4-oxadiazol-5-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 437202

2-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-N,N-dimethylaniline trifluoroacetate 412 203

2-[(4,4-difluoro-1-{[5- fluoro-2-(1,3-thiazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline trifluoroacetate 470204

4-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-5-phenyl- 1,3-thiazol-2-amine trifluoroacetate 467 205

2-[(4,4-difluoro-1-{[3-(1H- pyrrol-1- yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline trifluoroacetate 434 206

2-({4,4-difluoro-1-[(3- thiophen-3- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 451 207

2-({1-[(2,2-difluoro-1,3- benzodioxol-4-yl)carbonyl]-4,4-difluoropiperidin-3- yl}oxy)quinoline trifluoroacetate 449 208

3-{[4,4-difluoro-3- (quinolin-2-yloxy)piperidin- 1-yl]carbonyl}-N,N-dimethylaniline trifluoroacetate 412 209

2-({(3S)-4,4-difluoro-1-[(3- thiophen-2- ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 451 210

2-{[(3S,4R)-4-fluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 391 211

2-{[(3S,4R)-4-fluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline trifluoroacetate 418212

2-{[(3S)-4,4-difluoro-1-{[2- (trifluoromethyl)imidazo[1,2- a]pyridin-8-yl]carbonyl}piperidin-3- yl]oxy}quinoline hydrochloride 477 213

2-{[(3S)-4,4-difluoro-1-{[5- (trifluoromethyl)imidazo[1,2- a]pyridin-8-yl]carbonyl}piperidin-3- yl]oxy}quinoline hydrochloride 477 214

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-6-iodoquinoline trifluoroacetate 535 215

2-{[(3S)-4,4-difIuoro-1- (5,6,7,8- tetrahydroimidazo[1,2- a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 413 216

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[2,3-c]pyridin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 217

2-({4,4-difluoro-1-[(3- methyl[1,2,4]triazolo[4,3- a]pyridin-8-yl)carbonyl]piperidin-3- yl}oxy)quinoline trifluoroacetate 424 218

2-{[(3S)-1-(1H- benzimidazol-2-ylcarbonyl)- 4,4-difluoropiperidin-3-yl]oxy}quinoline trifluoroacetate 409 219

2-{[(3S)-4,4-difluoro-1- (1H-pyrrolo[3,2-c]pyridin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 409 220

2-({(3S)-4,4-difluoro-1-[(1- methyl-1H-pyrazolo[3,4- b]pyridin-3-yl)carbonyl]piperidin-3- yl}oxy)quinoline 424 221

2-{[4,4-difluoro-1- ([1,2,3]triazolo[1,5- a]pyridin-3-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 222

2-({4,4-difluoro-1-[(1- methyl-1H-indol-5- yl)carbonyl]piperidin-3-yl}oxy)quinoline trifluoroacetate 422 223

2-{[(3S)-4,4-difluoro-1- (5H-pyrrolo[2,3-b]pyrazin-6-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 410 224

7-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,2-dihydro- 3H-indazol-3-one trifluoroacetate 425 225

4-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3- benzoxazol-2(3H)-one trifluoroacetate 426 226

6-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-2,3-dihydro- 1H-isoindol-1-one trifluoroacetate 424 227

6-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3- benzoxazol-2(3H)-one trifluoroacetate 426 228

5-{[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3-dihydro- 2H-benzimidazol-2-one trifluoroacetate 425229

(3S,4R)-4-fluoro-3- (quinolin-2- ylamino)piperidin-1-yl](imidazo[1,2-a]pyridin-8- yl)methanone 390 230

[(3S)-4,4-difluoro-3- (quinolin-2-yloxy)piperidin-1-yl][3-(1,3-thiazol-4- yl)phenyl]methanone trifluoroacetate 452 231

(6-chloro-1H-imidazo[4,5- c]pyridin-4-yl)[(3S)-4,4-difluoro-3-(quinolin-2- yloxy)piperidin-1- yl]methanone hydrochloride444

TABLE 2 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 2, butsubstituting the appropriate acid for 3-(1H-1,2,3-triazol-1-yl)benzoicacid (Step 2) and the appropriate alkylating agent for2-chlorobenzothiazole (Step 3), as described in the foregoing ReactionSchemes and Examples. The requisite starting materials were commerciallyavailable, described in the literature or readily synthesized by oneskilled in the art of organic synthesis from commercially availablereagents using conventional reactions without undue experimentation. MSExample Structure Name (M + 1) 232

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinazoline trifluoroacetate 437233

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoxaline 437 234

6-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]thieno[2,3- b]pyridinetrifluoroacetate 442 235

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]-1,3-benzothiazole 442 236

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-6-fluoroquinoline trifluoroacetate 427236

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}-1,3-benzothiazole 442 237

5-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}thieno[3,2- b]pyridine 442 238

6-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}thieno[2,3- b]pyridine 442 239

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]quinoline-3- carbonitrile 461 240

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}-6-fluoroquinoline 454 241

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}-8-methylquinolinetrifluoroacetate 450 242

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}-8-fluoroquinoline 454 243

8-chloro-2-{[(3S)-4,4- difluoro-1-{[3-(1H-1,2,3- triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline 470 244

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]-6,7-dihydro-5H-cyclopenta[b]pyridine trifluoroacetate 426 245

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]-5- (trifluoromethyl)pyridine 454246

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}quinoline-3- carbonitrile 461 247

8-{[(3S)-3-{[6-chloro-5- (trifluoromethyl)pyridin-2- yl]oxy}-4,4-difluoropiperidin-1- yl]carbonyl}imidazo[1,2- a]pyridine 461 248

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-1,3-benzothiazole trifluoroacetate 415249

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-8-methylquinoline trifluoroacetate 423250

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-8-fluoroquinoline trifluoroacetate 427251

8-chloro-2-{[(3S)-4,4- difluoro-1-(imidazo[1,2- a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}quinoline trifluoroacetate 443 252

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-4,6-difluoro-1,3- benzothiazoletrifluoroacetate 451 253

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-4,5,6-trifluoro-1,3- benzothiazoletrifluoroacetate 469 254

8-{[(3S)-3-(6,7-dihydro-5H- cyclopenta[b]pyridin-2-yloxy)-4,4-difluoropiperidin- 1-yl]carbonyl}imidazo[1,2- a]pyridinetrifluoroacetate 399 255

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinazoline trifluoroacetate 509 256

2-{[(3S)-4,4-difluoro-1-{[3- (1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}-5,6,7,8- tetrahydroquinazoline441 257

5-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]pyrazolo[1,5- a]pyrimidine 426258

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]-1,3-benzoxazole 426 259

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy][1,3]thiazolo[5,4- b]pyridine 443260

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy][1,3]thiazolo[5,4- c]pyridinetrifluoroacetate 443 261

2-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine 443 262

2-{[(3S)-4,4-difluoro-1- (imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3- yl]oxy}-4-(trifluoromethyl)- 1,3-benzothiazoletrifluoroacetate 483 263

3-[(4,4-difluoro-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl)oxy]isoquinoline 436

Example 264

1-(3-{[(3S)-4,4-Difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-fluorophenyl)-3-methylimidazolidin-2-one

Sodium hydride (54.73 mg, 0.118 mmol) was added to a solution of1-(3-{[(35S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-fluorophenyl)imidazolidin-2-one(20.0 mg, 0.039 mmol) in DMSO (1 mL) and the solution was stirred atambient temperature for 0.5 h. Iodomethane (0.0037 mL, 0.059 mmol) wasadded and the solution was stirred for 16 h. The reaction mixture waspurified directly by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desiredfractions were concentrated to yield the title compound as thetrifluoroacetate salt. MS: m/z=485 (M+1); HRMS: m/z=485.1781 (M+1);calculated m/z=485.1795 (M+1) for C₂₅H₂₄F₃N₄O₃.

Example 265

[(3S)-4,4-Difluoro-3-{[6-methyl-5-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl](imidazo[1,2-a]pyridin-8-yl)methanone

A degassed solution of[(3S)-3-{[6-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-4,4-difluoropiperidin-1-yl](imidazo[1,2-a]pyridin-8-yl)methanone(Example XX, 20.0 mg, 0.043 mmol), trimethylboroxin (0.049 mL, 0.174mmol, 50 wt % solution), tetrakis(triphenylphosphine)palladium (5.02 mg,4.34 mol), and sodium carbonate (0.043 mL, 0.087 mmol) in dioxane (1 mL)was heated for 4 d at 100° C. After 1 d, additional trimethylboroxin(0.049 mL, 0.174 mmol) and tetrakis(triphenylphosphine)palladium (5.02mg, 4.34 μmol) were added. The reaction mixture was filtered andpurified directly by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The desiredfractions were concentrated to yield the title compound as thetrifluoroacetate salt. MS: m/z=441 (M+1); HRMS: m/z=441.1352 (M+1);calculated m/z=441.1344 (M+1) for C₂₀H₁₈F₅N₄O₂.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula I:

wherein: A is selected from the group consisting of phenyl, napthyl andheteroaryl; B is selected from the group consisting of phenyl, napthyland heteroaryl; X is —NR⁴—, —O— or —CH₂—, wherein R⁴ is selected fromthe group consisting of: (1) hydrogen, (2) C₁₋₆alkyl, (3)—C₃₋₆cycloalkyl, and (4) —CF₃; R^(1a), R^(1b) and R^(1c) may be absentif the valency of A does not permit such substitution and areindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) andwhere the alkyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl,where the cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (6) —(C═O)_(m)—C₂₋₄alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹³, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where thephenyl or napthyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R¹⁴,(c) C₃₋₆alkenyl, which is unsubstituted or substituted with R¹⁴, (d)C₃₋₆alkynyl, which is unsubstituted or substituted with R¹⁴, (e)C₃₋₆cycloalkyl which is unsubstituted or substituted with R¹⁴, (f)phenyl, which is unsubstituted or substituted with R¹⁴, and (g)heterocycle, which is unsubstituted or substituted with R¹⁴, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R^(2a), R^(2b) and R^(2c) may be absent if the valency ofB does not permit such substitution and are independently selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornapthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) 4C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R³ is selected from the group consisting of: (1) hydrogen, (2) halogen,and (3) C₁₋₆alkyl, where the alkyl is unsubstituted or substituted withone or more substituents selected from R¹⁴, R¹³ is selected from thegroup consisting of: (1) halogen, (2) hydroxyl, (3)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹⁴, (4)—O_(n)—(C₁₋₃)perfluoroalkyl, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, wherethe cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (6) —(C═O)_(m)—C₂₋₄alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹⁴, (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹⁴, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where thephenyl or napthyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) oxo;R¹⁴ is selected from the group consisting of: (1) hydroxyl, (2) halogen,(3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6)—O(C═O)—C₁₋₆alkyl, (7) —NH—C₁₋₆alkyl, (8) phenyl, (9) heterocycle, (10)—CO₂H, and (11) —CN; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 of the formula Ib:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 of the formula Ib′:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1 or a pharmaceutically acceptable salt thereof wherein A is selectedfrom the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazinyl,pyrazolyl, thiazolyl, isothiazolyl, thiophneyl, benzimidazolyl,azabenzimidazolyl, benzimidazolonyl, indazolyl, dihydroindazolonyl,azaindazolyl, indolyl, indolonyl, dihydroisoindolonyl, azaindolyl,benzofuranyl, dihyrobenzofuranyl, benzoxazolyl, benzoxazolonyl,benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,imidazopyridinyl, tetrahydroimidazopyridinyl, imidazopyrazinyl,imidazopyridazinyl, imidazothiazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl,triazolopyridinyl, triazolopyrimidinyl, and tetrazolopyridinyl.
 6. Thecompound of claim 1 or a pharmaceutically acceptable salt thereofwherein B is selected from the group consisting of: (1) phenyl, (2)quinoline, (3) isoquinoline, (4) benzoxazole, (5) thienopyridine, (6)pyridine, (7) quinazoline, (8) pyrimidine, (9) benzothiazole, and (10)quinoxaline.
 7. The compound of claim 1 or a pharmaceutically acceptablesalt thereof wherein R^(1a), R^(1b) and R^(1c) are independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl or napthyl, (5) —O—C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl, (6)heteroaryl, wherein heteroaryl is selected from triazolyl, oxazolyl,imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, tetrazolyl,imidazolidinonyl, oxazolidinonyl, pyrrolidinonyl, pyridyl, andpyrimidinyl, which is unsubstituted or substituted with halogen,hydroxyl or C₁₋₆alkyl, (7) phenyl, which is unsubstituted or substitutedwith halogen, hydroxyl or C₁₋₆alkyl, (8) C₃₋₆cycloalkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl, and (9)—CN.
 8. The compound of claim 1 or a pharmaceutically acceptable saltthereof wherein R^(2a), R^(2b) and R^(2c) are independently selectedfrom the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl,(4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl, (5) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl or phenyl, and (6) —CN.
 9. Thecompound of claim 1 or a pharmaceutically acceptable salt thereofwherein R³ is fluoro.
 10. A compound which is selected from the groupconsisting of: (3S)-(4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl)(2,6-difluoro-3-methoxyphenyl)methanone;(S)-(3-(1H-1,2,3-triazol-1-yl)phenyl)(3-(benzo[d]thiazol-2-yloxy)-4,4-difluoropiperidin-1-yl)methanone;2-[(4,4-difluoro-1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(3S)-(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-({4,4-difluoro-1-[(5-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(4-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(1-{[5-bromo-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-4,4-difluoropiperidin-3-yl)oxy]quinoline;2-[(1-{[5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-4,4-difluoropiperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[3-(1,3-thiazol-4-yl)pyridin-2-yl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1,3-thiazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1,3-thiazol-5-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1,3-oxazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1-methyl-1H-pyrazol-4-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-{[4,4-difluoro-1-(quinolin-6-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}phenol;2-({4,4-difluoro-1-[(2-fluorophenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(2-methylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-{[2-(trifluoromethyl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-({4,4-difluoro-1-[(3-methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({1-[(2-ethoxyphenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(3-methylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}benzonitrile2-({1-[(3-cyclopropylphenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-{[2-(methylsulfanyl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1H-imidazol-1-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1H-1,2,4-triazol-5-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1H-imidazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(1H-pyrazol-4-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-({4,4-difluoro-1-[(2-methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-{[2-(1H-1,2,4-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(methylsulfanyl)-1H-benzimidazol-7-yl]carbonyl}piperidin-3-yl)oxy]quinoline;2-{[4,4-difluoro-1-(1H-indazol-7-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({4,4-difluoro-1-[(2-pyrazin-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(3-methyl-1H-indol-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-1[2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl-piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-fluoro-6-(1,3-thiazol-4-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[5-fluoro-2-(1,3-thiazol-4-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-{[4,4-difluoro-1-(imidazo[1,2-a]pyrazin-5-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[4,4-difluoro-1-([1,2,4]triazolo[1,5-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;3-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-2-fluorophenol;2-[(4,4-difluoro-1-1[4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl)oxy]quinoline;[3-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)phenyl]methanol;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[2-(4-methyl-1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-{[4,4-difluoro-1-(tetrazolo[1,5-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({4,4-difluoro-1-[(4-pyrrolidin-1-ylpyridin-2-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(1H-pyrazol-1-yl)phenol;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(1H-imidazol-4-yl)phenol;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(1,3-thiazol-4-yl)phenol;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(1H-pyrazol-3-yl)phenol;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(1,3-oxazol-4-yl)phenol;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-(1,3-oxazol-2-yl)phenol;2-[(1-{[2-chloro-5-(1H-pyrazol-1-yl)phenyl]carbonyl}-4,4-difluoropiperidin-3-yl)oxy]quinoline;2-({4,4-difluoro-1-[(5-furan-2-yl-1-methyl-1H-pyrazol-3-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-1[3-(1,3-oxazol-5-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-({1-[(2,6-dimethoxyphenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-({1-[(5-chloro-2-methylphenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-({1-[(2,5-difluorophenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(2-fluoro-6-methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[1-(2,3-dihydro-1-benzofuran-7-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-({4,4-difluoro-1-[(2-fluoro-3-methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({1-[(2,3-difluorophenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(2-methoxy-5-methylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-{[3-(1H-imidazol-1-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-({4,4-difluoro-1-[(3-furan-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(3-methoxy-5-methylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({4,4-difluoro-1-[(2-methyl-1-benzofuran-7-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[4,4-difluoro-1-(1H-imidazo[4,5-c]pyridin-7-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3 S)-4,4-difluoro-1-(pyrazolo[1,5-a]pyridin-7-ylcarbonyl)piperidin-3-yl]oxy}quinoline; 2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(2-fluoro-5-methoxyphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[4,4-difluoro-1-(imidazo[2,1-b][1,3]thiazol-6-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(2-methyl-2H-indazol-3-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-1-(1,2-benzisoxazol-3-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(2-phenylpyridin-3-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({(3S)-4,4-difluoro-1-[(4-phenylpyridin-3-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3 S)-4,4-difluoro-1-(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline; 2-{[(3S)-4,4-difluoro-1-(pyrazolo[1,5-a]pyridin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline; 2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[2,3-b]pyridin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[3,2-b]pyridin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-indol-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-indazol-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(1-methyl-1H-indazol-3-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,5-a]pyridin-1-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,5-a]pyridin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(5H-pyrrolo[2,3-b]pyrazin-7-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;4-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}phenyl)-1,3-thiazol-2-amine;2-{[(3S)-4,4-difluoro-1-{[2-(1H-tetrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[2-fluoro-5-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[2-fluoro-5-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}quinoline;2-{[(3S)-1-{[5-bromo-2-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[2-fluoro-5-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1,2,4-oxadiazol-3-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1,3-oxazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;(3S)-(4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;2-({(3S)-1-[(2,6-difluoro-3-methoxyphenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-{[3-fluoro-5-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-fluoro-5-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}quinoline;2-{[(3S)-1-{[3-bromo-5-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[4-(1H-1,2,3-triazol-1-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[4-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-1-[(3-chloroimidazo[1,2-a]pyridin-8-yl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1,3-thiazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-pyrazol-3-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(2-methyl-1,3-thiazol-4-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[4-(1H-imidazol-1-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,4-triazol-5-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(2-pyridin-3-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-1-(1H-benzimidazol-4-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(1-methyl-1H-indazol-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;1-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}phenyl)-imidazolidin-2-one;2-{[(3S)-4,4-difluoro-1-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(3-phenylpyridin-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-pyrazol-4-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-1-[(2,5-dimethoxyphenyl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-imidazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(3-phenylpyridin-2-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-1-(1H-benzimidazol-5-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-indazol-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[2-(5-methyl-2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-1-{[2-chloro-5-(4H-1,2,4-triazol-4-yl)phenyl]carbonyl}-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-4-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-1-(1,3-benzoxazol-4-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(2-pyridin-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3 S,4S)-4-fluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3 S,4S)-4-fluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[6-(1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[4-(1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]oxy}quinoline;1-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-fluorophenyl)imidazolidin-2-one;2-{[(3S)-4,4-difluoro-1-{[2-(1H-1,2,3-triazol-5-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyrazin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-imidazo[4,5-c]pyridin-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(3-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({(3S)-4,4-difluoro-1-[(2-methyl-1H-benzimidazol-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({(3S)-4,4-difluoro-1-[(6-fluoro-1H-benzimidazol-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({(3S)-4,4-difluoro-1-[(2-pyridin-4-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-6-fluoro-1,3-benzothiazole;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-6-fluoro-1,3-benzothiazole;7-{[(3S)-4,4-difluoro-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl]carbonyl}pyrazolo[1,5-a]pyridine;2-({(3S)-4,4-difluoro-1-[(6-fluoroimidazo[1,2-a]pyridin-8-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({(3S)-4,4-difluoro-1-[(2-pyrimidin-5-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-{[4-(1,3-oxazol-2-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]oxy}quinoline;7-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3-benzoxazol-2(3H)-one;2-{[(3S)-4,4-difluoro-1-{[2-(trifluoromethyl)-1H-benzimidazol-4-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-1-[(7-chloroimidazo[1,2-a]pyridin-8-yl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;3-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}phenyl)-1,3-oxazolidin-2-one;2-({(3S)-1-[(6-chloroimidazo[1,2-a]pyridin-8-yl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrazolo[4,3-c]pyridin-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrazolo[3,4-b]pyridin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[7-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(3-iodoimidazo[1,2-a]pyridin-8-yl)carbonyl]piperidin-3-yl}oxy)quinoline;3-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-fluorophenyl)-1,3-oxazolidin-2-one;1-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-fluorophenyl)pyrrolidin-2-one;2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[2,3-c]pyridin-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-indol-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[2,3-b]pyridin-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-([1,2,3]triazolo[1,5-a]pyridin-7-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[3,2-c]pyridin-4-ylcarbonyl)piperidin-3-yl]oxy}quinoline;1-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4,6-difluorophenyl)imidazolidin-2-one;4-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3-dihydro-2H-indol-2-one;2-({(3S)-4,4-difluoro-1-[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)carbonyl]piperidin-3-yl}oxy)quinoline; 2-{[(3S)-4,4-difluoro-1-(1H-imidazo[4,5-c]pyridin-6-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-1-(1,3-benzothiazol-5-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-imidazo[4,5-b]pyridin-6-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3 S)-4,4-difluoro-1-(pyrazolo[1,5-a]pyridin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline; 2-{[(3S)-4,4-difluoro-1-(1H-indazol-5-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-indazol-6-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3 S)-1-(2,1-benzisothiazol-3-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-{[(3 S)-1-(2,1-benzisoxazol-3-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-({4,4-difluoro-1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[4,4-difluoro-1-([1,2,4]triazolo[4,3-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({4,4-difluoro-1-[(6-methylimidazo[2,1-b][1,3]thiazol-3-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-[(4,4-difluoro-1-{[4-(2H-1,2,3-triazol-2-yl)isothiazol-3-yl]carbonyl}piperidin-3-yl)oxy]quinoline;2-[(4,4-difluoro-1-{[3-methyl-5-(2H-1,2,3-triazol-2-yl)isothiazol-4-yl]carbonyl}piperidin-3-yl)oxy]quinoline;2-{[1-(1H-benzotriazol-5-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-[(4,4-difluoro-1-{[3-(1H-1,2,4-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-{[4,4-difluoro-1-(imidazo[1,5-a]pyridin-5-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[4,4-difluoro-1-(pyrazin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[4,4-difluoro-1-(pyrimidin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[1-(biphenyl-2-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-[(4,4-difluoro-1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-{[4,4-difluoro-1-(1H-indol-7-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3 S)-4,4-difluoro-1-(pyrazolo[1,5-a]pyrimidin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline; 2-{[(3S)-4,4-difluoro-1-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[3,2-b]pyridin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,5-b]pyridazin-7-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-b]pyridazin-2-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(1-methyl-1H-benzimidazol-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({(3S)-4,4-difluoro-1-[(1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1,2,4-oxadiazol-5-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-N,N-dimethylaniline;2-[(4,4-difluoro-1-{[5-fluoro-2-(1,3-thiazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;4-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-5-phenyl-1,3-thiazol-2-amine;2-[(4,4-difluoro-1-{[3-(1H-pyrrol-1-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;2-({4,4-difluoro-1-[(3-thiophen-3-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-({1-[(2,2-difluoro-1,3-benzodioxol-4-yl)carbonyl]-4,4-difluoropiperidin-3-yl}oxy)quinoline;3-{[4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-N,N-dimethylaniline;2-({(3S)-4,4-difluoro-1-[(3-thiophen-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S,4R)-4-fluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S,4R)-4-fluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-{[5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]carbonyl}piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-6-iodoquinoline;2-1 [(3 S)-4,4-difluoro-1-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[2,3-c]pyridin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({4,4-difluoro-1-[(3-methyl[1,2,4]triazolo[4,3-a]pyridin-8-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-1-(1H-benzimidazol-2-ylcarbonyl)-4,4-difluoropiperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(1H-pyrrolo[3,2-c]pyridin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-({(3S)-4,4-difluoro-1-[(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[4,4-difluoro-1-([1,2,3]triazolo[1,5-a]pyridin-3-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{(4,4-difluoro-1-[(1-methyl-1H-indol-5-yl)carbonyl]piperidin-3-yl}oxy)quinoline;2-{[(3S)-4,4-difluoro-1-(5H-pyrrolo[2,3-b]pyrazin-6-ylcarbonyl)piperidin-3-yl]oxy}quinoline;7-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,2-dihydro-3H-indazol-3-one;4-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3-benzoxazol-2(3H)-one;6-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-2,3-dihydro-1H-isoindol-1-one;6-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3-benzoxazol-2(3H)-one;5-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-1,3-dihydro-2H-benzimidazol-2-one;(3S,4R)-4-fluoro-3-(quinolin-2-ylamino)piperidin-1-yl](imidazo[1,2-a]pyridin-8-yl)methanone;[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl][3-(1,3-thiazol-4-yl)phenyl]methanone;(6-chloro-1H-imidazo[4,5-c]pyridin-4-yl)[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]methanone;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinazoline2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoxaline6-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]thieno[2,3-b]pyridine;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]-1,3-benzothiazole2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-6-fluoroquinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-1,3-benzothiazole;5-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}thieno[3,2-b]pyridine;6-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}thieno[2,3-b]pyridine;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]quinoline;-3-carbonitrile; 2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-6-fluoroquinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-8-methylquinoline;2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-8-fluoroquinoline;8-chloro-2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]-6,7-dihydro-5H-cyclopenta[b]pyridine;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]-5-(trifluoromethyl)pyridine;2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}quinoline;-3-carbonitrile; 8-{[(3S)-3-{[6-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-4,4-difluoropiperidin-1-yl]carbonyl}imidazo[1,2-a]pyridine;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-1,3-benzothiazole;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-8-methylquinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-8-fluoroquinoline;8-chloro-2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}quinoline;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-4,6-difluoro-1,3-benzothiazole;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-4,5,6-trifluoro-1,3-benzothiazole;8-{[(3S)-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yloxy)-4,4-difluoropiperidin-1-yl]carbonyl}imidazo[1,2-a]pyridine;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinazoline; 2-{[(3S)-4,4-difluoro-1-{[3-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-5,6,7,8-tetrahydroquinazoline;5-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]pyrazolo[1,5-a]pyrimidine;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]-1,3-benzoxazole;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy][1,3]thiazolo[5,4-b]pyridine;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy][1,3]thiazolo[5,4-c]pyridine;2-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine;2-{[(3S)-4,4-difluoro-1-(imidazo[1,2-a]pyridin-8-ylcarbonyl)piperidin-3-yl]oxy}-4-(trifluoromethyl)-1,3-benzothiazole;3-[(4,4-difluoro-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)oxy]isoquinoline;1-(3-{[(3S)-4,4-difluoro-3-(quinolin-2-yloxy)piperidin-1-yl]carbonyl}-4-fluorophenyl)-3-methylimidazolidin-2-one;and [(3S)-4,4-difluoro-3-{[6-methyl-5-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl](imidazo[1,2-a]pyridin-8-yl)methanone;or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 12. A method for treatinginsomnia in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof.